tbuckley/cabot-search huggingface dataset:
<i>TET2</i>-mutant clonal hematopoiesis and risk of gout
Authors: Mridul Agrawal, Abhishek Niroula, Pierre Cunin, Marie McConkey, Veronica Shkolnik, Peter G. Kim, Waihay J. Wong, Lachelle D. Weeks, Amy E. Lin, Peter G. Miller, Christopher J. Gibson, Aswin Sekar, Inga-Marie Schaefer, Donna Neuberg, Richard M. Stone, Alexander G. Bick, Md Mesbah Uddin, Gabriel K. Griffin, Siddhartha Jaiswal, Pradeep Natarajan, Peter A. Nigrovic, Deepak A. Rao, Benjamin L. Ebert
Journal: Blood (2022)

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
49P Impact of nutritional factors in response and survival of patients with gestational trophoblastic neoplasia
Authors: K. Roque Perez, M.A. Galvez Nino, M.W. Castro, H.D. Vallejos, R.E. Ruiz, N.I. Valdiviezo Lama, O. Coanqui Gonzales, M. Olivera, J. Perez, A. Lopez, C. Velarde, R.A. De Mello, L.A. Mas Lopez
Journal: Annals of Oncology (2022)
Design, preparation and pharmacodynamics of ICG-Fe(Ⅲ) based HCPT nanocrystals against cancer
Authors: Qiongzhe Ren, Xuefeng Tang, Yi Lu, Qing Li, Zhiqian Liao, Shinan Jiang, Haoli Zhang, Zhigang Xu, Lei Luo
Journal: Asian Journal of Pharmaceutical Sciences (2022)

The use of nanocrystal technology to manufacture drug delivery systems intended to enhance therapeutic efficacy has attracted the attention of the pharmaceutical industry. However, the clinical application of nanocrystal drugs for injection is restricted by Ostwald ripening and the large-scale use of stabilizers such as polysorbate and lecithin, which have potential toxicity risks including hemolysis and allergies. Here, we designed an amorphous nanocrystal drug complex (IHNC), which is stabilizer-free and composed of indocyanine green (ICG) framework loading with a chemotherapeutic agent of 10-hydroxycamptothecin (HCPT). Considering the possibility of industrial manufacturing, IHNC was simply prepared with the assistance of ferric ion (III) via supramolecular assembly strategy. The theoretical result of Materials Studio simulation indicated that the prepared ICG-Fe(III) framework showed a stable spherical structure with the appropriate cavity for encapsulating the two drugs of HCPT and ICG with equal mass ratio. The IHNC was stable at physiological pH, with excellent PTT/PDT efficacy, and in vivo probing characteristics. The nanoscale size and reductive stimuli-responsiveness can be conducive to drug accumulation into the tumor site and rapid unloading of cargo. Moreover, such combination therapy showed synergistic photo/chemotherapy effect against 4T1 breast cancer and its tumor inhibition rate even up to 79.4%. These findings demonstrated that the nanocrystal drug delivery strategy could avoid the use of stabilizers and provide a new strategy for drug delivery for combination therapy.
43P Malignant bowel obstruction in advanced ovarian cancer: A retrospective analysis of patients supported with parenteral nutrition
Authors: R.K.K. Wight, A.D. Murphy, J. Bower, R.D. Morgan, L. Flanagan, S. Maycock, S. Lal, A. Teubner, A. Abraham, C. Mitchell, J. Hasan, G. Jayson, A.R. Clamp, Z. Salih
Journal: Annals of Oncology (2022)
The oral ferroportin inhibitor vamifeport improves hemodynamics in a mouse model of sickle cell disease
Authors: Naja Nyffenegger, Rahima Zennadi, Natarajaswamy Kalleda, Anna Flace, Giada Ingoglia, Raphael M. Buzzi, Cédric Doucerain, Paul W. Buehler, Dominik J. Schaer, Franz Dürrenberger, Vania Manolova
Journal: Blood (2022)

Abstract Sickle cell disease (SCD) is an inherited hemolytic anemia caused by a single point mutation in the β-globin gene of hemoglobin that leads to synthesis of sickle hemoglobin (HbS) in red blood cells (RBCs). HbS polymerizes in hypoxic conditions, leading to intravascular hemolysis, release of free hemoglobin and heme, and increased adhesion of blood cells to the endothelial vasculature, which causes painful vaso-occlusion and organ damage. HbS polymerization kinetics are strongly dependent on the intracellular HbS concentration; a relatively small reduction in cellular HbS concentration may prevent HbS polymerization and its sequelae. We hypothesized that iron restriction via blocking ferroportin, the unique iron transporter in mammals, might reduce HbS concentration in RBCs, thereby decreasing hemolysis, improving blood flow, and preventing vaso-occlusive events. Indeed, vamifeport (also known as VIT-2763), a clinical-stage oral ferroportin inhibitor, reduced hemolysis markers in the Townes model of SCD. The RBC indices of vamifeport-treated male and female Townes mice exhibited changes attributable to iron-restricted erythropoiesis: decreased corpuscular hemoglobin concentration mean and mean corpuscular volume, as well as increased hypochromic and microcytic RBC fractions. Furthermore, vamifeport reduced plasma soluble VCAM-1 concentrations, which suggests lowered vascular inflammation. Accordingly, intravital video microscopy of fluorescently labeled blood cells in the microvasculature of Townes mice treated with vamifeport revealed diminished adhesion to the endothelium and improved hemodynamics. These preclinical data provide a strong proof-of-concept for vamifeport in the Townes model of SCD and support further development of this compound as a potential novel therapy in SCD.
Epiglottic Polymorphous Adenocarcinoma With Multiple Bone Metastases Detected by 68Ga-FAPI PET/CT
Authors: Yizhen Pang, Tinghua Meng, Weizhi Xu, Lei Kong, Haojun Chen
Journal: Clinical Nuclear Medicine (2022)

Polymorphous adenocarcinoma (PAC) is generally an indolent tumor that mostly commonly affects the minor salivary gland. Polymorphous adenocarcinoma with distant metastases is extremely rare. In this case, we reported 18 F-FDG and 68 Ga-FAPI PET/CT imaging findings in a rare case of epiglottic PAC with multiple bone metastases. 68 Ga-FAPI PET/CT showed superiority over 18 F-FDG PET/CT for detecting the primary and metastatic PAC. This case highlighted that 68 Ga-FAPI may be a promising radiopharmaceutical in the diagnosis of PAC, especially for detecting the PACs arising in uncommon sites.
44TiP ENGOT-ov65/KEYNOTE-B96: Phase III, randomized, double-blind study of pembrolizumab vs placebo + paclitaxel with optional bevacizumab for platinum-resistant recurrent ovarian cancer
Authors: N. Colombo, R.L. Coleman, X. Wu, F. Kose, R. Wenham, A. Sebastianelli, K. Hasegawa, E. Zsiros, T. De La Motte Rouge, M. Bidzinski, I. McNeish, J. Sehouli, J. Korach, P.R. Debruyne, J-W. Kim, A.C. De Melo, X. Peng, A.M. Bogusz, K. Yamada, B.J. Monk
Journal: Annals of Oncology (2022)
PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression
Authors: Hong‐Yong Cui, Wei Wei, Mei‐Rui Qian, Ruo‐Fei Tian, Xin Fu, Hong‐Wei Li, Gang Nan, Ting Yang, Peng Lin, Xi Chen, Yu‐Meng Zhu, Bin Wang, Xiu‐Xuan Sun, Jian‐Hua Dou, Jian‐Li Jiang, Ling Li, Shi‐Jie Wang, Zhi‐Nan Chen
Journal: Cancer Communications (2022)

The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA-associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target.Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient-derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target.PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers. Mechanistic studies showed that c-Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR-mitogen-activated protein kinase (MAPK) signaling activation, which resulted in FOS-related antigen 1 (FRA-1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels.PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer. c-Myc-driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR-MAPK-FRA-1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.
Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency
Authors: Sotiria Tavoulari, Denis Lacabanne, Chancievan Thangaratnarajah, Edmund R.S. Kunji
Journal: Trends in Endocrinology and Metabolism (2022)

Citrin deficiency is a pan-ethnic and highly prevalent mitochondrial disease with three different stages: neonatal intrahepatic cholestasis (NICCD), a relatively mild adaptation stage, and type II citrullinemia in adulthood (CTLN2). The cause is the absence or dysfunction of the calcium-regulated mitochondrial aspartate/glutamate carrier 2 (AGC2/SLC25A13), also called citrin, which imports glutamate into the mitochondrial matrix and exports aspartate to the cytosol. In citrin deficiency, these missing transport steps lead to impairment of the malate-aspartate shuttle, gluconeogenesis, amino acid homeostasis, and the urea cycle. In this review, we describe the geological spread and occurrence of citrin deficiency, the metabolic consequences and use our current knowledge of the structure to predict the impact of the known pathogenic mutations on the calcium-regulatory and transport mechanism of citrin.
Immunogenicity of a single dose of BNT162b2, ChAdOx1 nCoV-19, or CoronaVac against SARS-CoV-2 delta and omicron variants among previously infected adults: A randomized trial
Authors: Suvimol Niyomnaitham, Zheng Quan Toh, Paul Vincent Licciardi, Patimaporn Wongprompitak, Kanjana Srisutthisamphan, Katherine Kradangna Copeland, Kulkanya Chokephaibulkit
Journal: Journal of Infection (2022)
Enasidenib vs conventional care in older patients with late-stage mutant-<i>IDH2</i> relapsed/refractory AML: a randomized phase 3 trial
Authors: Stéphane de Botton, Pau Montesinos, Andre C. Schuh, Cristina Papayannidis, Paresh Vyas, Andrew H. Wei, Hans Ommen, Sergey Semochkin, Hee-Je Kim, Richard A. Larson, Jaime Koprivnikar, Olga Frankfurt, Felicitas Thol, Jörg Chromik, Jenny Byrne, Arnaud Pigneux, Xavier Thomas, Olga Salamero, Maria Belen Vidriales, Vadim Doronin, Hartmut Döhner, Amir T. Fathi, Eric Laille, Xin Yu, Maroof Hasan, Patricia Martin-Regueira, Courtney D. DiNardo
Journal: Blood (2022)

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.
Leveraging Therapy-Specific Polygenic Risk Scores to Predict Restrictive Lung Defects in Childhood Cancer Survivors
Authors: Cindy Im, Yan Yuan, Eric D. Austin, Dennis C. Stokes, Matthew J. Krasin, Andrew M. Davidoff, Yadav Sapkota, Zhaoming Wang, Kirsten K. Ness, Carmen L. Wilson, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Daniel A. Mulrooney, Yutaka Yasui
Journal: Cancer Research (2022)

Abstract Therapy-related pulmonary complications are among the leading causes of morbidity among long-term survivors of childhood cancer. Restrictive ventilatory defects (RVD) are prevalent, with risks increasing after exposures to chest radiotherapy and radiomimetic chemotherapies. Using whole-genome sequencing data from 1,728 childhood cancer survivors in the St. Jude Lifetime Cohort Study, we developed and validated a composite RVD risk prediction model that integrates clinical profiles and polygenic risk scores (PRS), including both published lung phenotype PRSs and a novel survivor-specific pharmaco/radiogenomic PRS (surPRS) for RVD risk reflecting gene-by-treatment (GxT) interaction effects. Overall, this new therapy-specific polygenic risk prediction model showed multiple indicators for superior discriminatory accuracy in an independent data set. The surPRS was significantly associated with RVD risk in both training (OR = 1.60, P = 3.7 × 10−10) and validation (OR = 1.44, P = 8.5 × 10−4) data sets. The composite model featuring the surPRS showed the best discriminatory accuracy (AUC = 0.81; 95% CI, 0.76–0.87), a significant improvement (P = 9.0 × 10−3) over clinical risk scores only (AUC = 0.78; 95% CI: 0.72–0.83). The odds of RVD in survivors in the highest quintile of composite model-predicted risk was ∼20-fold higher than those with median predicted risk or less (OR = 20.01, P = 2.2 × 10−16), exceeding the comparable estimate considering nongenetic risk factors only (OR = 9.20, P = 7.4 × 10−11). Inclusion of genetic predictors also selectively improved risk stratification for pulmonary complications across at-risk primary cancer diagnoses (AUCclinical = 0.72; AUCcomposite = 0.80, P = 0.012). Overall, this PRS approach that leverages GxT interaction effects supports late effects risk prediction among childhood cancer survivors. Significance: This study develops a therapy-specific polygenic risk prediction model to more precisely identify childhood cancer survivors at high risk for pulmonary complications, which could help improve risk stratification for other late effects.
Deep learning with weak annotation from diagnosis reports for detection of multiple head disorders: a prospective, multicentre study
Authors: Yuchen Guo, Yuwei He, Jinhao Lyu, Zhanping Zhou, Dong Yang, Liangdi Ma, Hao-tian Tan, Changjian Chen, Wei Zhang, Jianxing Hu, Dongshan Han, Guiguang Ding, Shixia Liu, Hui Qiao, Feng Xu, Xin Lou, Qionghai Dai
Journal: The Lancet Digital Health (2022)

A large training dataset with high-quality annotations is necessary for building an accurate and generalisable deep learning system, which can be difficult and expensive to prepare in medical applications. We present a novel deep-learning-based system, requiring no annotator but weak annotation from a diagnosis report, for accurate and generalisable performance in detecting multiple head disorders from CT scans, including ischaemia, haemorrhage, tumours, and skull fractures.Our system was developed on 104 597 head CT scans from the Chinese PLA General Hospital, with associated textual diagnosis reports. Without expert annotation, we used keyword matching on the reports to automatically generate disorder labels for each scan. The labels were inaccurate because of the unreliable annotator-free strategy and inexact because of scan-level annotation. We proposed RoLo, a novel weakly supervised learning algorithm, with a noise-tolerant mechanism and a multi-instance learning strategy to address these issues. RoLo was tested on retrospective (2357 scans from the Chinese PLA General Hospital), prospective (650 scans from the Chinese PLA General Hospital), cross-centre (1525 scans from the Brain Hospital of Hunan Province), cross-equipment (1484 scans from the Chinese PLA General Hospital), and cross-nation (CQ500 public dataset from India) test datasets. Four radiologists were tested on the prospective test dataset before and after viewing system recommendations to assess whether the system could improve diagnostic performance.The area under the receiver operating characteristic curve for detecting the four disorder types was 0·976 (95% CI 0·976-0·976) for retrospective, 0·975 (0·974-0·976) for prospective, 0·965 (0·964-0·966) for cross-centre, and 0·971 (0·971-0·972) for cross-equipment test datasets, and 0·964 (0·964-0·966) for CQ500 (with only haemorrhage and fracture). The system achieved similar performance to four radiologists and helped to improve sensitivity and specificity by 0·109 (95% CI 0·086-0·131) and 0·022 (0·017-0·026), respectively.Without expert annotated data, our system achieved accurate and generalisable performance for head disorder detection. The system improved the diagnostic performance of radiologists. Because of its accuracy and generalisability, our computer-aided diganostic system could be used in clinical practice to improve the accuracy and efficiency of radiologists in different hospitals.National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.
The retinal pigmentation pathway in human albinism: Not so black and white
Authors: Reinier Bakker, Ellie L. Wagstaff, Charlotte C. Kruijt, Eszter Emri, Clara D.M. van Karnebeek, Michael B. Hoffmann, Brian P. Brooks, Camiel J.F. Boon, Lluis Montoliu, Maria M. van Genderen, Arthur A. Bergen
Journal: Progress in Retinal and Eye Research (2022)

Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities, including foveal hypoplasia and chiasmal misrouting. Combining our data with those of the literature, we propose a single functional genetic retinal signalling pathway that includes all 22 currently known human albinism disease genes. We hypothesise that defects affecting the genesis or function of different intra-cellular organelles, including melanosomes, cause syndromic forms of albinism (Hermansky-Pudlak (HPS) and Chediak-Higashi syndrome (CHS)). We put forward that specific melanosome impairments cause different forms of oculocutaneous albinism (OCA1-8). Further, we incorporate GPR143 that has been implicated in ocular albinism (OA1), characterised by a phenotype limited to the eye. Finally, we include the SLC38A8-associated disorder FHONDA that causes an even more restricted "albinism-related" ocular phenotype with foveal hypoplasia and chiasmal misrouting but without pigmentation defects. We propose the following retinal pigmentation pathway, with increasingly specific genetic and cellular defects causing an increasingly specific ocular phenotype: (HPS1-11/CHS: syndromic forms of albinism)-(OCA1-8: OCA)-(GPR143: OA1)-(SLC38A8: FHONDA). Beyond disease genes involvement, we also evaluate a range of (candidate) regulatory and signalling mechanisms affecting the activity of the pathway in retinal development, retinal pigmentation and albinism. We further suggest that the proposed pigmentation pathway is also involved in other retinal disorders, such as age-related macular degeneration. The hypotheses put forward in this report provide a framework for further systematic studies in albinism and melanin pigmentation disorders.
10P 10-year survival outcome and patterns of failure analysis of patients with localized adenocarcinoma cervix: Our experience from a tertiary cancer care center
Authors: D.K. Simson, S. Mitra, H. Khurana, S. Barik, K. Dobriyal, A. Krishnan, P. Umesh, S. Pathi, A. Dewan
Journal: Annals of Oncology (2022)